EXCEED THE SPACE PROVIDED. The overall goal of the General Clinical Research Center (GCRC) at Dallas is to provide an optimal environment for patient-oriented investigation which leads to an improved understanding of the disease process, allows better methods of diagnosis and treatment, fosters interdisciplinary collaboration, and offers training in clinical investigation. Major patient-oriented research activities of the GCRC include: to characterize the phenotype and metabolic abnormalities, and elucidation of genetic defects in patients with congenital generalized and familial partial iipodystrophies; to study pathophysiology of absorptive hypercalciuria, including the clinical significance of recently discovered absorptive hypercalciuria-related adenyl cyclase (AHRAC) gene, effect of dietary animal protein excess in causing hypercalciuria and to elucidate dietary calcium-oxalate interaction; to study influence of recently discovered polymorphisms in the genes affecting sterol transport (ABCG5 and ABCG8) on plasma low density lipoprotein cholesterol levels, sterol concentrations and ratios, and body pools of sterols; to study the pathophysiology, particularly related to insulin resistance in gouty diathesis (renal stone formation associated with gout), and the effects of improving insulin sensitivity in reversing the biochemical defects; to determine the significance of Tyr594Met polymorphism in epithelial channel locus (ENaC) in patients with essential hypertension and to study blood pressure response to ENaC or mineralocorticoid receptor blockage using spironolactone and/or amiioride; to understand the role of adrenocortical hyposensitivity in alcohol dependence, its persistence over time and relationship to subsequent alcohol intake, its emotional and structural correlates and underlying basis of reduced glucocorticoid synthesis; and to study metabolic basis of cystic fibrosis related diabetes mellitus from the contribution of elevated hepatic glucose production and hepatic insulin resistance.